Studies On The Synthesis Of Vindoline And Montanine-type Alkaloids

(-)-Vindoline, a highly functionalized pentacyclic indole alkaloids, originally isolated from Catharanthus roseus G. Don, is an important biosynthetic precursor of the well-known clinically used antitumor agents vinblastine and vincristine. Both vinblastine and vincristine are produced in extremely small quantities in the plant Vinca rosea. Total synthesis of these compounds attracts wide attention among synthetic chemists. Since the synthetic route of vinblastine via the coupling of vindoline and catharanthine has been established, it is of importance to design efficient strategies towards the synthesis of vindoline.The montanine-type alkaloids, a small class of Amaryllidaceae alkaloids, are isolated from various Amaryllidaceae species and characterized by the presence of a5,11-methanomorphanthridine framework Alkaloids of this group possess similar structural features except for the hydroxyl and/or methoxy groups at C2and C3or at C3and C4. A number of biological properties have been attributed to these alkaloids including anticonvulsive, antidepressive, anxiolytic and weak hypertensive activities.Vindoline and montanine-type alkaloids in racemic as well as optically active forms have already been synthesized. However, practical and flexible synthetic routes towards these compounds are still in demand. So studies towards the synthesis of vindoline and montanine-type alkaloids, especially the synthesis of vindoline, are of importance both in organic chemistry and medicinal chemistry. This thesis describes the synthetic studies on vindoline and montanine-type alkaloids.Four chapters are included in the thesis. In the first chapter, the total synthesis of montanine-type alkaloids are reviewed. IBD-mediated dearomatization of phenol for alkaloid synthesis is also described briefly.New approaches towards the synthesis of vindoline are discussed in Chapter2, including Michael addition cascade reaction, the palladium-mediated sequential arylation-allylation and the intramolecular Friedel-Crafts reaction as the key transformation for the construction of the benzylic quaternary carbon center for vindoline. The enantioselective synthesis of a key block for vindoline was obtained, and an intermediate for the synthesis of huperzine-like analogues was synthesized, a number of sulfonamide compounds were synthesized.In chapter3, the synthesis of the montanine alkaloids is described. Montabuphine was isolated in1995by Codina. The stereochemistry for C4a-H is uncertain. Two possible structures for montabuphine were deduced based on Banwell's recent work. A new and flexible synthetic route was established and the montanine-like alkaloids were synthesized. Our result demonstrated that the structure of montabuphine needs to be revised. Studies on the synthesis of lycorine, mesembrine, crinine and lycoricidine are also discussed in this chapter.Experiment procedure, physical and spectral data for compounds described in Chapter2and Chapter3are recorded in Chapter4.